Presentation is loading. Please wait.

Presentation is loading. Please wait.

New Paradigms and Landscape Changes in Atrial Fibrillation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular SpecialistApplying Landmark.

Similar presentations


Presentation on theme: "New Paradigms and Landscape Changes in Atrial Fibrillation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular SpecialistApplying Landmark."— Presentation transcript:

1

2 New Paradigms and Landscape Changes in Atrial Fibrillation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular SpecialistApplying Landmark Trials to the Front Lines of Cardiology Practice National Experts in Cardiovascular Medicine Illuminate and Debate Program Chairman and Moderator Peter Libby, MD, FACC Chief, Cardiovascular Medicine Brigham and Womens Hospital Mallinckrodt Professor of Medicine Harvard Medical School Boston, Massachusetts

3 CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Boehringer-Ingelheim Faculty disclosures: Listed in program syllabus Welcome and Program Overview

4 Program Faculty Peter Libby, MD, FACC Program Chairman and Moderator Chief, Cardiovascular Medicine Brigham and Womens Hospital Mallinckrodt Professor of Medicine Harvard Medical School Boston, Massachusetts Jonathan L. Halperin, MD Mount Sinai School of Medicine Director, Clinical Cardiology Service The Zena and Michael A. Wiener Cardiovascular Institute The Marie-Josée and Henry R. Kravis Center for Cardiovascular Health New York, New York Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Boston University Medical Center Boston, Massachusetts Jeffrey I. Weitz, MD, FRCP, FACP Professor of Medicine and Biochemistry McMaster University Director, Henderson Research Center Canada Research Chair in Thrombosis Heart and Stroke Foundation J.F. Mustard Chair in Cardiovascular Research Ontario, Canada

5 Challenges in Stroke Prevention for Patients with Atrial Fibrillation Achieving Balance Between Prevention of Thromboembolism and Risk of Bleeding Risk Stratification, Current Guidelines and Therapeutic Choices New Frontiers in Atrial Fibrillation Jonathan L. Halperin, MD Professor of Medicine (Cardiology) Mount Sinai School of Medicine Director, Clinical Cardiology Services The Zena and Michael A. Wiener Cardiovascular Institute The Marie-Josée and Henry R. Kravis Center for Cardiovascular Health

6 Atrial Fibrillation A Substantial Threat to the Brain Affects Affects ~4% of people aged >60 years ~9% of those aged >80 years ~9% of those aged >80 years 5%/year stroke rate 5%/year stroke rate 12%/year for those with prior stroke 12%/year for those with prior stroke $ billions annual cost for stroke care $ billions annual cost for stroke care AF-related strokes have worse outcomes AF-related strokes have worse outcomes AF identifies millions of people with a five-fold increased risk of stroke

7 Natural History of Lone Atrial Fibrillation No Cardiopulmonary Disease; <60 Years Old Kopecky S, et al. N Engl J Med 1987; 317: Patients Mean Age = years Follow-up 0.35%/yr Stroke 0.40%/yr Mortality

8 Stroke Risk in Atrial Fibrillation Untreated Control Groups of Randomized Trials Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449. Stroke Rate (% per year) Age (years)

9 Anticoagulation in Atrial Fibrillation Stroke Risk Reductions Hart R, et al. Ann Intern Med 2007;146:857. WarfarinBetterControlBetter AFASAK SPAF BAATAF CAFA SPINAF EAFT 100% 50% 0 -50% -100% Aggregate

10 Anticoagulation in Atrial Fibrillation The Standard of Care for Stroke Prevention WarfarinBetterControlBetter AFASAK SPAF BAATAF CAFA SPINAF EAFT 100% 50% 0 -50% -100% Aggregate Terminated early Double-blind; Men only Unblinded Unblinded Unblinded 2 o prevention; Unblinded Hart R, et al. Ann Intern Med 2007;146:857.

11 Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reduction Antiplatelet drugs vs. Placebo Warfarin vs. Placebo/Control 100% 50% 0 -50% 6 Trials n = 2,900 8 Trials n = 4,876 TreatmentBetterTreatmentWorse Hart R, et al. Ann Intern Med 2007;146:857.

12 Efficacy of Warfarin in Trials vs. Practice Stroke Risk Reductions Warfarin vs. No anticoagulation Warfarin vs. Placebo/Control 100% 50% 0 -50% 6 Trials n = 2,900 Medicare cohort n = 23,657 TreatmentBetterTreatmentWorse Hart R, et al. Ann Intern Med 2007;146:857 Birman-Deych E. Stroke 2006; 37: 1070–1074

13 Intracerebral Hemorrhage >10% of intracerebral hemorrhages (ICH) occur in patients on antithrombotic therapy >10% of intracerebral hemorrhages (ICH) occur in patients on antithrombotic therapy Aspirin increases the risk by ~ 40% Aspirin increases the risk by ~ 40% Warfarin (INR 2–3) doubles the risk to 0.3– 0.6%/year Warfarin (INR 2–3) doubles the risk to 0.3– 0.6%/year ICH during anticoagulation is catastrophic ICH during anticoagulation is catastrophic Hart RG, et al. Stroke 2005;36:1588 The Most Feared Complication of Antithrombotic Therapy

14 Risk Stratification in AF Stroke Risk Factors High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

15 High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA Moderate-Risk Factors Age >75 yearsAge >75 years HypertensionHypertension Diabetes mellitusDiabetes mellitus Heart failure or LV functionHeart failure or LV function Risk Stratification in AF Stroke Risk Factor s Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

16 High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA Moderate-Risk Factors Age >75 years Age >75 years Hypertension Hypertension Diabetes mellitus Diabetes mellitus Heart failure or LV function Heart failure or LV function Less Validated Risk Factors Age 65–75 years Coronary artery disease Coronary artery disease Female gender Female gender Thyrotoxicosis Thyrotoxicosis Risk Stratification in AF Stroke Risk Factors Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

17 High-Risk Factors Mitral stenosis Mitral stenosis Prosthetic heart valve Prosthetic heart valve History of stroke or TIA History of stroke or TIA Moderate-Risk Factors Age >75 years Age >75 years Hypertension Hypertension Diabetes mellitus Diabetes mellitus Heart failure or LV function Heart failure or LV function Less Validated Risk Factors Age 65–75 years Coronary artery disease Coronary artery disease Female gender Female gender Thyrotoxicosis Thyrotoxicosis Dubious Factors Duration of AF Pattern of AF Pattern of AF (persistent vs. paroxysmal) Left atrial diameter Left atrial diameter Risk Stratification in AF Stroke Risk Factors Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

18 The CHADS 2 Index Stroke Risk Score for Atrial Fibrillation Congestive Heart failure 1 32 Hypertension 1 65 Age >75 years 1 28 Diabetes mellitus 1 18 Stroke or TIA 2 10 Moderate-High risk> Low risk VanWalraven C, et al. Arch Intern Med 2003; 163:936. VanWalraven C, et al. Arch Intern Med 2003; 163:936. * Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published). Prevalence (%)* Score (points)

19 Nonvalvular Atrial Fibrillation PriorStroke/TIA Age > 75 years Hypertension FemaleDiabetes Heart Failure LVEF LVEF Stroke Rate (%/year) Hart RG et al. Neurology 2007; 69: 546. Stroke Rates Without Anticoagulation According to Isolated Risk Factors

20 Van Walraven C, et al. Arch Intern Med 2003; 163:936. Go A, et al. JAMA 2003; 290: Gage BF, et al. Circulation 2004; 110: Risk of Stroke (%/year) Score(points) 3%/year Approximate Risk threshold for Anticoagulation The CHADS 2 Index Stroke Risk Score for Atrial Fibrillation

21 Risk Stratification and Anticoagulation Stroke Reduction with Warfarin Instead of Aspirin Number of patients Needed-to-treat to prevent 1 stroke/year EAFT Study Group. Lancet 1993; 324:1255. Zabalgoitia M, et al. J Am Coll Cardiol 1998; 31: CHADS 2 Score ~

22 Antithrombotic Therapy for Atrial Fibrillation ACC/AHA/ESC Guidelines 2006 Risk Factor Recommended Therapy No risk factors CHADS 2 = 0 Aspirin, mg qd One moderate risk factor CHADS 2 = 1 Aspirin, mg/d or Warfarin (INR , target 2.5) Any high risk factor or >1 moderate risk factor CHADS 2 >2 or Mitral stenosis Warfarin (INR , target 2.5) Prosthetic valve Warfarin (INR , target 3.0)

23 " Actually, it's more of a guideline than a rule. Bill Murray in Ghostbusters (1984), Bill Murray in Ghostbusters (1984), relaxing his rule "never to get involved with possessed people" in response to Sigourney Weaver's seductive advances.

24 Patient Selection for Anticoagulation Additional Considerations Risk of bleeding Risk of bleeding Newly anticoagulated vs. established therapy Newly anticoagulated vs. established therapy Availability of high-quality anticoagulation management program Availability of high-quality anticoagulation management program Patient preferences Patient preferences

25 The ACTIVE Trial Clopidogrel + Aspir in Atrial Fibrillation + Risk Factors VKA (INR 2-3) Clopidogrel + Aspirin Aspirin + Placebo Clopidogrel + Aspirin Double-blind Superiority n = 7,554 Open-label Non-inferiority n = 6,706 Anticoagulation-eligible OAC Contraindications or Unwilling Irbesartan, 300 mg/d vs. Placebo n = 9,016 Primary outcome: Stroke, systemic embolism, MI or cardiovascular death ACTIVE - W ACTIVE - A ACTIVE - I Risk Factors: Age 75, hypertension, prior stroke/TIA, LVEF<45%, PAD, age CAD or diabetes

26 The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk Factors ACTIVE – W ACTIVE – W VKA (INR 2-3) Clopidogrel + Aspirin Aspirin + Placebo Clopidogrel + Aspirin Double-blind Superiority n = 7,554 Open-label Non-inferiority n = 6,706 Anticoagulation-eligible OAC Contraindications or Unwilling Irbesartan, 300 mg/d vs. Placebo n = 9,016 ACTIVE - A ACTIVE - I

27 Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reductions 100% 50% 0 -50% ACTIVE-W Anticoagulation vs. Aspirin + Clopidogrel Anticoagulation vs. Antiplatelet drugs 7 Trials n = 4,232 n = 6,706 WarfarinBetter Antiplatelet Rx Better Connolly S, et al. Lancet 2006; 367:1903. Hart R, et al. Ann Intern Med 2007;146:857.

28 Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reductions 100% 50% 0 -50% Warfarin vs. Aspirin + Clopidogrel WarfarinBetter Antiplatelet Rx Better Prior OAC VKA-naïve Connolly S, et al. Lancet 2006; 367:1903. All patients

29 Major Hemorrhage in Relation to Prior Anticoagulant Therapy: ACTIVE-W Interaction p=0.028 Yes Yes Anticoagulant Therapy at Entry No No Connolly S, et al. Lancet 2006; 367:1903. Event Rate (%/year) Starters Switchers

30 The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk Factors ACTIVE – W ACTIVE – W VKA (INR 2-3) Clopidogrel + Aspirin Aspirin + Placebo Clopidogrel + Aspirin Double-blind Superiority n = 7,554 Open-label Non-inferiority n = 6,706 Anticoagulation-eligible OAC Contraindications or Unwilling Irbesartan, 300 mg/d vs. Placebo n = 9,016 ACTIVE - A ACTIVE - I Connolly SJ, et al. N Engl J Med 2009; 360:2066.

31 Risk factor for bleeding* 23% Physician judgment against anticoagulation for patient 50% Patient preference only 26% * Inability to comply with INR monitoring * Predisposition to falling or head trauma * Persistent hypertension >160/100 mmHg * Previous serious bleeding on VKA * Severe alcohol abuse within 2 years * Peptic ulcer disease * Thrombocytopenia * Chronic need for NSAID Connolly SJ, et al. N Engl J Med 2009; 360:2066. The ACTIVE Trial Reasons for Exclusion from Anticoagulation

32 ACTIVE-A Total Stroke Rate s Connolly SJ, et al. N Engl J Med 2009; 360: (2.4%/year) 408 (3.3%/year) Cumulative Incidence 28% RRR HR 0.72 (95% CI, 0.62–0.83) p < Aspirin Clopidogrel + Aspirin Years

33 The ACTIVE Trials Stroke Rates and Risk Reductions Connolly SJ, et al. Lancet 2006; 367:1903. Connolly SJ, et al. N Engl J Med 2009; 360:2066. TreatmentVKAC+AAspirin ACTIVE W (Annual Rate) ~ ACTIVE A (Annual Rate) ~ RRR versus Aspirin -58%-28%~ RRR versus C+A -42%~~ VKA = oral anticoagulant C+A = clopidogrel + aspirin

34 Investigational Anticoagulant Targets TFPI (tifacogin) Idraparinux Rivaroxaban Apixaban Edoxaban LY YM150 Betrixaban TAK 42 Dabigatran ORALPARENTERAL DX-9065a Otamixaban Xa IIa TF/VIIa XIX IXa VIIIa Va II (thrombin) FibrinFibrinogen AT APC (drotrecogin alfa) sTM (ART-123) Adapted from Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7. TTP889 APC activated protein C AT antithrombin sTM soluble thrombomodulin TF tissue factor FPI tissue factor pathway inhibitor

35 Dose, Concentration, or Intensity of Anticoagulation Thrombosis Bleeding Safe Therapeutic Range Thrombosis Bleeding The Ideal Anticoagulant Wide Therapeutic Margin

36 Emerging Anticoagulants Regulatory Issues Open-label vs. blinded trial design Open-label vs. blinded trial design Issues related to active-control trial design Issues related to active-control trial design How many trials are needed? How many trials are needed? Preventing use for unapproved indications Preventing use for unapproved indications Assessing patient-oriented outcomes Assessing patient-oriented outcomes

37 Alternatives to Anticoagulation Atrial Fibrillation Restoration and maintenance of sinus rhythm Antiarrhythmic drug therapyAntiarrhythmic drug therapy Catheter ablationCatheter ablation Maze operationMaze operation Current approaches Emerging (investigational) approaches Obliteration of the left atrial appendage Trans-catheter occluding devicesTrans-catheter occluding devices Thoracoscopic epicardial plicationThoracoscopic epicardial plication AmputationAmputation

38 Strokes after Conversion to NSR Rate vs. Rhythm Control Trials n Rate control Rhythm control RR (95% CI) p AFFIRM4,9175.7%7.3% 1.28 ( ) 0.12 RACE5225.5%7.9% 1.44 ( ) 0.44 STAF2661.0%3.0% 3.01 ( ) 0.52 PIAF2520.8%0.8% 1.02 ( ) 0.49 Total5,9575.0%6.5% 1.28 ( ) 0.08 Verheugt F, et al. J Am Coll Cardiol 2003;41(suppl):130A.

39 AFFIRM Trial Stroke Rates 74% of all strokes were proven ischemic 74% of all strokes were proven ischemic 44% occurred after stopping warfarin 44% occurred after stopping warfarin 28% in patients taking warfarin with INR <2.0 28% in patients taking warfarin with INR <2.0 42% occurred during documented AF 42% occurred during documented AF Wyse AG, et al. N Engl J Med 2002; 347: 1825 Wyse AG, et al. N Engl J Med 2002; 347: 1825.

40 ATHENA Trial Dronedarone vs. Placebo in Patients with AF Hohnloser SH, et al. N Engl J Med 2009; 360: Event Placebo (%/y) Dronedarone (%/y) HR (95% CI) P Stroke Stroke or TIA Fatal stroke Stroke Rates (Secondary Analysis )

41 Percutaneous LAA Occlusion The WATCHMAN ® Device Syed T, Halperin JL. Nature Clin Prac Cardiovasc Med 2007; 4:428 Holmes DR, et al. Lancet 2009; 374: 534

42 Alternatives to Anticoagulation Atrial Fibrillation Restoration and maintenance of sinus rhythm Antiarrhythmic drug therapyAntiarrhythmic drug therapy Catheter ablationCatheter ablation Maze operationMaze operation Current approaches Emerging (investigational) approaches Obliteration of the left atrial appendage Trans-catheter occluding devicesTrans-catheter occluding devices Thoracoscopic epicardial plicationThoracoscopic epicardial plication AmputationAmputation Is atrial fibrillation the cause of stroke or a marker of a population at risk?

43 Atrial Fibrillation and Thromboembolism The Next Challenges Better tools to stratify bleeding risk Better tools to stratify bleeding risk Noninvasive imaging and biomarkers of inflammation and thrombosis to predict clinical events and guide therapy Noninvasive imaging and biomarkers of inflammation and thrombosis to predict clinical events and guide therapy Confirming successful rhythm control over time Confirming successful rhythm control over time Targeted therapy to prevent AF in patients at risk Targeted therapy to prevent AF in patients at risk Defining role and risk stratification strategies for non-monitored, oral anticoagulants Defining role and risk stratification strategies for non-monitored, oral anticoagulants

44 From Fermented Sweet Clover to Molecular Targeting of Coagulation The Promise of New Approaches The Goal: To bring effective therapy to many more patients and prevent thousands of strokes.

45 Atrial Fibrillation Case Study

46 An 82-year-old man with hypertension and diabetes has permanent atrial fibrillation An 82-year-old man with hypertension and diabetes has permanent atrial fibrillation He has a history of spinal stenosis and walks with a walker He has a history of spinal stenosis and walks with a walker

47 Question 1: Which regimen would you prescribe for prophylaxis against thromboembolism? a.Warfarin (INR ) b.Warfarin (INR ) c.Aspirin, 81 mg daily d.Aspirin, 81 mg + clopidogrel, 75 mg daily e.No antithrombotic therapy Atrial Fibrillation Case Study

48 Atrial Fibrillation Case Study Assessment of Thromboembolic Risk Van Walraven C, et al. Arch Intern Med 2003; 163: 936. Go A, et al. JAMA 2003; 290: Gage BF, et al. Circulation 2004; 110: Risk of Stroke (%/year) Score(points)

49 Question 2: What if you learn that he has tripped and fallen twice in the past two years? a.Warfarin (INR ) b.Warfarin (INR ) c.Aspirin, 81 mg daily d.Aspirin, 81 mg + clopidogrel, 75 mg daily e.No antithrombotic therapy Atrial Fibrillation Case Study

50 Question 3: If the oral direct thrombin inhibitor dabigatran were available and FDA-approved for stroke prevention in AF, in this patient with a history of tripping you would treat with: a.Warfarin (INR ) b.Warfarin (INR ) c.Dabigatran 110 mg P.O. B.I.D d.Dabigatran 150 mg P.O. B.I.D. e. Aspirin, 81 mg + clopidogrel, 75 mg daily f.No antithrombotic therapy Atrial Fibrillation Case Study

51 Atrial Fibrillation Case Study Anticoagulation in Patients at Risk of Falls

52 …persons taking warfarin must fall about 295 (535/1.81) times in 1 year for warfarin not to be the optimal therapy…

53 Atrial Fibrillation Case Study ICH in Patients with AF Prone to Falls Gage BF, et al. Am J Med 2005; 118:612. The risk of ICH was 2.8%/year in patients at high risk of falls and 1.1 in other patients. The risk of ICH was 2.8%/year in patients at high risk of falls and 1.1 in other patients. Warfarin was associated with an increased risk of mortality among those with ICH (30 day mortality = 52 vs. 34%, p = 0.007). Warfarin was associated with an increased risk of mortality among those with ICH (30 day mortality = 52 vs. 34%, p = 0.007).Factor Hazard ratio (95% CI) P value High-risk for falls 1.9 ( ) Prior stroke 2.2 ( ) < Prior bleed 1.8 ( ) < Neuropsychiatric impairment 1.4 ( ) Hazard ratios of independent predictors of intracranial hemorrhage

54 Atrial Fibrillation Case Study Outcomes in Patients with AF Prone to Falls Gage BF, et al. Am J Med 2005; 118:612. CHADS 2 score Hazard ratio (95% CI) P value Recommended antithrombotic therapy (0.56, 1.72) 0.94 Aspirin or nil (0.61, 0.91) 0.004Anticoagulant Hazard ratio of warfarin for composite outcomeout-of-hospital death or hospitalization for stroke, MI, or hemorrhagein 1245 patients at high risk for falls

55 Summary of Case Study The risk of intracranial hemorrhage is increased in patients who fall. The risk of intracranial hemorrhage is increased in patients who fall. The use of oral anticoagulation does not predict ICH, but mortality is higher among patients on anticoagulants who develop ICH. The use of oral anticoagulation does not predict ICH, but mortality is higher among patients on anticoagulants who develop ICH. The risk of mortality due to ICH is offset by the reduction in ischemic events achieved with anticoagulation in elderly patients with AF at high risk of thromboembolism. The risk of mortality due to ICH is offset by the reduction in ischemic events achieved with anticoagulation in elderly patients with AF at high risk of thromboembolism. Better risk-stratification instruments are needed. Better risk-stratification instruments are needed.

56 Stroke Prevention in High Risk Populations Optimizing Warfarin Therapy in Challenging Patient Populations New Frontiers in Atrial Fibrillation Elaine M. Hylek, MD, MPH Associate Professor of Medicine Department of Medicine Director, Thrombosis Clinic and Anticoagulation Service Boston University Medical Center Boston, Massachusetts

57 Prevalence of AF by Age Feinberg WM. Arch Intern Med. 1995;155(5):469–473 Framingham Study Cardiovascular Health Study Mayo Clinic Study Western Australia Study Prevalence (%) Age (years)

58 Atrial Fibrillation Morbidity and Mortality 4- to 5-fold increased risk of stroke 4- to 5-fold increased risk of stroke Doubling of the risk for dementia Doubling of the risk for dementia Tripling of risk for heart failure Tripling of risk for heart failure 40 to 90% increased risk for overall mortality 40 to 90% increased risk for overall mortality Risk of stroke in AF patients by age group Risk of stroke in AF patients by age group –1.5% in 50 to 59 year age group –23.5% in 80 to 89 year age group Benjamin EJ, et al. Circulation 2009;119:

59 The graying population will slowly, radically transform society. Richard Suzman, NIA The graying population will slowly, radically transform society. Richard Suzman, NIA More than 37 million people are age 65. More than 37 million people are age 65. By 2030, this number will exceed 70 million. By 2030, this number will exceed 70 million. By 2040, those aged 75 years will exceed the By 2040, those aged 75 years will exceed the population 65 to 74 years old. By 2050, 12%, or 1 in 8 Americans, will be By 2050, 12%, or 1 in 8 Americans, will be age 75 or older.

60 * Coronary heart disease, heart failure, stroke and hypertension Prevalence of CVD* in Adults by Age and Sex (NHANES: ) Source: NCHS and NHLBI Age

61 Pharmacokinetic and Pharmacodynamic Changes with Aging Metabolism Metabolism Generally, lower drug doses are required to achieve the same effect Generally, lower drug doses are required to achieve the same effect Receptor numbers, affinity, or post-receptor cellular effects may change Receptor numbers, affinity, or post-receptor cellular effects may change Overall decline in metabolic capacity Overall decline in metabolic capacity Decreased liver mass Decreased liver mass Decreased oxidative metabolism through P450 system decreased clearance of drugs Decreased oxidative metabolism through P450 system decreased clearance of drugs

62 Kidney Function and Age Andres and Tobin, 1976 Age (years) Standard Creatine Clearance ml/min/

63 Prevalence of Dementia North America: 6.9% prevalence; 63% increase ; 151% increase

64 Polypharmacy in the Elderly Elderly = 12% of population; Elderly = 12% of population; 32% of prescriptions 32% of prescriptions Average of 6 prescription medications; Average of 6 prescription medications; 1 to 3.5 over-the-counter drugs Average nursing home patient Average nursing home patient takes 7 medications Average American senior spends Average American senior spends $670/year for pharmaceuticals

65 Adverse Drug Reactions Adverse Drug Reactions About 15% of hospitalizations in the elderly are related to adverse drug reactions About 15% of hospitalizations in the elderly are related to adverse drug reactions The risk of adverse drug reactions increases with the number of prescription medications The risk of adverse drug reactions increases with the number of prescription medications

66 Polypharmacy and Non-adherence Strongest predictor of non-adherence is Strongest predictor of non-adherence is the number of medications Non-adherence rates estimated 25-50% Non-adherence rates estimated 25-50% Intentional about 75% of the time Intentional about 75% of the time Changes in regimen made by patients to: - Increase convenience - Reduce adverse effects or - Decrease refill expense

67 Hazards of Anticoagulant Medications #1 in 2003 and 2004 in the number of mentions of deaths for drugs causing adverse effects in therapeutic use 1 #1 in 2003 and 2004 in the number of mentions of deaths for drugs causing adverse effects in therapeutic use 1 Warfarin-6% of 702,000 ADEs treated in ED per year; 17% require hospitalization 1 Warfarin-6% of 702,000 ADEs treated in ED per year; 17% require hospitalization 1 21 million warfarin prescriptions in 1998>>>31 million in million warfarin prescriptions in 1998>>>31 million in The incidence AC-related intracranial hemorrhage quintupled during this time period 3 The incidence AC-related intracranial hemorrhage quintupled during this time period 3 1 Wysowski DK, et al. Arch Intern Med. 2007;167: Budnitz DS, et al. JAMA. 2006;296: Flaherty ML, et al. Neurology. 2007;68:

68 Odds Ratio INR Stroke Intracranial Bleed 1.0 Fuster et al. J Am Coll Cardiol. 2001;38: Ischemic Stroke and Intracranial Bleeding Adjusted Odds in Relation to Intensity of Anticoagulation

69 Warfarin Dosing is Complex Factors that Correlate w/ Warfarin Dose Age Age Body surface area (BSA) or weight Body surface area (BSA) or weight Amiodarone Amiodarone Other drugs (e.g. acetaminophen) Other drugs (e.g. acetaminophen) Race Race Sex Sex Plasma vitamin K level Plasma vitamin K level Decompensated CHF Decompensated CHF Chemotherapy Chemotherapy Genetic status Genetic status Other Factors (up to 40%) Age, Sex, Weight (10-20%) CYP2C9 (up to 15%) VKORC1 (up to 25%)

70 ACTIVE W Trial VKA vs dual antiplatelet Rx Circulation 2008;118. Connolly SJ for Active W Investigators Minimum threshold TTR necessary to realize benefit of warfarin: 58% 58%

71 Comparison of Outcomes Among Patients Randomized to Warfarin According to Anticoagulant Control Results From SPORTIF III and V TTR 75% TTR 75%Outcome TTR < 60% TTR 60-75% TTR>75% Mortality, % Major Bleed, % Stroke/SEE,% Arch Intern Med White HD, Gruber M, Feyzi J, Kaatz S, Tse H, Husted S, Albers G

72 Major Hemorrhage Rates Randomized Trials INR Target ICHMajorAge AFI SPAF II AFFIRM RE-LY Observational INR Target ICHMajorAge Van der Meer, et al. (1993) Palareti, et al (1996) Go, et al (2003)

73 Historical trials SPORTIF III/V ACTIVE W RE-LY Year published N3,7637,3276,70618,113 Age, yrs Female29%31%33%37% Prior stroke 5%21%15%20% Hypertension45%77%83%79% CHR26%18%21%32% Diabetes13%18%21%23% CHADS 2 score NANA Baseline Characteristics AF Trials

74 Cumulative Incidence of Major Bleeding Hylek EM et al, Circulation 2007;115(21): Days of Warfarin Age =80 Cumulative Proportion with Major Hemorrhage First Year Among Patients Newly Starting Warfarin by Age

75 Risk of Stopping Therapy in the First Year Among Patients Newly Starting Warfarin by Age Hylek EM et al, Circulation 2007;115(21): Days of Warfarin Risk of Stopping Warfarin Age =80

76 Hemorrhage Thrombosis Optimizing Benefit and Reducing Risk

77 Strategies To Minimize Risk Of Hemorrhage Incidence of UGIB and LGIB increases with age. 70% of acute UGIB occur > 60 years of age. Differential mucosal effect of ASA by age Incidence of LGIB increases 200-fold from the 3 rd to 9 th decade of life: d iverticulosis, angiodysplasias, ischemic colitis, malignancy THE FACTS: THE FACTS:

78 Bleeding Risk Scores for Warfarin Therapy LowModerateHigh Kuijer et al. Arch Intern Med 1999;159: >3 1.6 x age x sex +2.2 x cancer with 1 point for 60, female or malignancy and 0 if none Beyth et al. Am J Med 1998;105: years old; GI bleed in last 2 weeks; previous stroke; comorbidities (recent MI, Hct 1.5) with 1 point for presence of each condition and 0 if absent Gage et al. Am Heart J 2006;151: HEMORR2HAGES score: liver/renal disease, ETOH abuse, malignancy, >75 years old, low platelet count or function, rebleeding risk, uncontrolled HTN, anemia, genetic factors (CYP2C9) risk of fall or stroke, with 1 point for each risk factor present with 2 points for previous bleed Shireman et al. Chest 2006;130: > <2.19>2.19 (0.49 x age >70) + (0.32 x female) + (0.58 x remote bleed) x recent bleed) x ETOH/drug abuse) + (0.27 x diabetes) + (0.86 x anemia) + (0.32 x antiplatelet drug use) with 1 point for presence of each and 0 if absent

79 Warfarin Dose by Age Derived from two independent ambulatory populations Garcia D, et al. Chest ;127: Female Male AgeAge Warfarin Weekly Dose, mg =90 =

80 Hylek et al, Ann Intern Med. 2001;135: Delay in INR Normalization with Increasing Age

81 Risk Factors for INR > 4.0 After Holding Two Doses of Warfarin Adjusted Odds Ratio Warfarin dose, weekly per 10 mg 0.87 ( ) Age, per decade 1.18 (1.01 – 1.38) Decompensated heart failure 2.79 (1.30 – 5.98) Active malignancy 2.48 (1.11 – 5.57) Index INR, per unit 1.25 (1.14 – 1.37)

82 Risk of UGIB with Different Combinations of Antithrombotic Agents Hallas J, et al. BMJ doi: /bmj AE Mean age=72 years

83 Evolving Role for Aspirin Meta-analysis of 10 trials that compared oral anticoagulant (OAC) therapy to ASA+OAC. Meta-analysis of 10 trials that compared oral anticoagulant (OAC) therapy to ASA+OAC. 4,180 patients with either heart valve, AF, or CAD 4,180 patients with either heart valve, AF, or CAD Combination therapy: Combination therapy: Lower incidence of thromboembolism (OR 0.66), but the benefits were limited to patients with valves (OR 0.27). Lower incidence of thromboembolism (OR 0.66), but the benefits were limited to patients with valves (OR 0.27). Did not benefit patients with AF (OR 0.99) or CAD (OR 0.69) nor did it influence all cause mortality. Did not benefit patients with AF (OR 0.99) or CAD (OR 0.69) nor did it influence all cause mortality. Did increase the risk of major bleeding (OR 1.43). Did increase the risk of major bleeding (OR 1.43). Dentali F, Douketis JD, Lim W, Crowther M. Arch Intern Med 2007; 167:

84 Strategies to Improve Quality of VKA-Based Anticoagulant Therapy Vigilant monitoring around all transitions in care Vigilant monitoring around all transitions in care Initiate lower doses in most susceptible patient subsets Initiate lower doses in most susceptible patient subsets Increase monitoring with medication changes Increase monitoring with medication changes Reinforce safety points with patients and caregivers Reinforce safety points with patients and caregivers Justify use of concomitant antiplatelet therapy Justify use of concomitant antiplatelet therapy

85 Summary Points and Conclusions Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage. Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage. Rates of ischemic stroke significantly exceed rates of ICH and major extracranial hemorrhage on OAC. Rates of ischemic stroke significantly exceed rates of ICH and major extracranial hemorrhage on OAC. Intensive efforts to optimize OAC will help to decrease major bleeding. Intensive efforts to optimize OAC will help to decrease major bleeding. Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t 1/2, lack of dietary interference, and fewer drug interactions. Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t 1/2, lack of dietary interference, and fewer drug interactions.

86 Atrial Fibrillation Case Study

87 85-year-old female with AF, HTN, HF, prior TIA, osteoarthritis and prior diverticular GIB six months ago, on warfarin, who presents to the ED with complaints of SOB for several days and black stools. 85-year-old female with AF, HTN, HF, prior TIA, osteoarthritis and prior diverticular GIB six months ago, on warfarin, who presents to the ED with complaints of SOB for several days and black stools. Medications: atenolol, lisinopril, lasix, warfarin, ASA Medications: atenolol, lisinopril, lasix, warfarin, ASA Most recent INR 3 weeks ago = 3.1 Most recent INR 3 weeks ago = 3.1 Atrial Fibrillation Patient Case Study

88 Question 1: This patients estimated stroke risk per year without warfarin is: a)5% b)12% c)20% d)None of the above Atrial Fibrillation Case Study

89 Exam:afebrile, HR , BP 154/90 lungs-bibasilar rales COR-irreg irreg ABD-nontender guaiac + ECG:AF with rapid VR CXR:mild pulmonary edema Labs:Hct=21, INR=8.0, Troponin - Physical Exam and Pertinent Data

90 Question 2: The most appropriate management strategy for this patient would be to: a)Stop both aspirin and warfarin – Resume aspirin only in one week b)Stop both aspirin and warfarin – Resume warfain c)Stop both aspirin and warfarin – Resume both warfarin and aspirin in one week d)Stop both aspirin and warfarin permanently Atrial Fibrillation Case Study

91 Question 3: The patients bleeding episode resolves, she is started back on warfarin, and she returns six months later with an hematocrit of 35 (her baseline). Her INR is 3.7. If dabigatran were approved by the FDA for SPAF, at this point you would: a)Stop warfarin and put the patient on clopidogrel and aspirin b)Adjust the warfarin to achieve an INR of c)Transition patient to dabigatran 110mg PO BID d)Transition patient to dabigatran 150 mg PO Bid e)Start aspirin only f)Stop all anticoagulation Atrial Fibrillation Case Study

92 The Emerging Role of New Oral Anticoagulants Landmark Trials That May Alter the Landscape of Stroke Prevention in AF New Frontiers in Atrial Fibrillation Jeffrey I. Weitz, MD, FRCP, FACP Professor of Medicine and Biochemistry McMaster University Director, Henderson Research Center Canada Research Chair in Thrombosis Heart and Stroke Foundation J.F. Mustard Chair in Cardiovascular Research

93 Overview of Presentation Limitations of warfarin Limitations of warfarin New oral anticoagulants New oral anticoagulants Role of new agents in AF Role of new agents in AF

94 Limitations of Warfarin LimitationConsequence Slow onset of action Overlap with a parenteral anticoagulant Genetic variation in metabolism Variable dose requirements Multiple food and drug interactions Frequent coagulation monitoring Narrow therapeutic index Frequent coagulation monitoring

95 New Oral Anticoagulants for Stroke Prevention in AF Direct Inhibitors of Factor Xa or Thrombin

96 Comparison of Features of New Oral Anticoagulants in Advanced Stages of Development FeaturesRivaroxabanApixaban Dabigatran Etexilate TargetXaXaIIa Molecular Weight ProdrugNoNoYes Bioavailability (%) Time to peak (h) 332 Half-life (h) Renal excretion (%) AntidoteNoneNoneNone

97 Comparison of Features of New Anticoagulants With Those of Warfarin FeaturesWarfarin New Agents OnsetSlowRapid DosingVariableFixed Food effect YesNo Drug interactions ManyFew MonitoringYesNo Half-lifeLongShort AntidoteYesNo

98 1.Oral factor Xa inhibitors have a better safety profile than oral thrombin inhibitors than oral thrombin inhibitors 2.Of the new oral anticoagulants, dabigatran etexilate is most advanced in development is most advanced in development 3.Oral factor Xa inhibitors can be safely given to patients with a creatinine clearance < 30 ml/min patients with a creatinine clearance < 30 ml/min 4.The prothrombin time can be used to monitor all of the new oral anticoagulants of the new oral anticoagulants 5.Fresh frozen plasma will reverse the anticoagulant effects of the new oral anticoagulants effects of the new oral anticoagulants Which of the Following Statements is true ?

99 RE-LY: A Non-inferiority Trial R Open Atrial Fibrillation with 1 Risk Factor Absence of Contraindications Conducted in 951 centers in 44 countries Warfarin Adjusted INR 2.0 – 3.0 N=6000 Dabigatran etexilate 110 mg BID N=6000 Dabigatran etexilate 150 mg BID N=6000 Blinded Event Adjudication OpenBlinded R

100 RE-LY: Baseline Characteristics Characteristic Dabigatran 110 mg Dabigatran 150 mg Warfarin Randomized Mean age (years) Male (%) CHADS2 score (mean) 0-1 (%) 0-1 (%) 2 (%) 2 (%) 3+ (%) 3+ (%) Prior stroke/TIA (%) Prior MI (%) CHF (%) Baseline ASA (%) Warfarin Naïve (%) Connolly et al., NEJM, 2009

101 RE-LY: Stroke or Systemic Embolism Dabigatran 110 vs. Warfarin Dabigatran 150 vs. Warfarin Non-inferiority p-value <0.001 <0.001 Superiority p-value <0.001 Margin = 1.46 HR (95% CI) Warfarin better Dabigatran better Connolly et al., NEJM, 2009

102 RE-LY: Annual Rates of Bleeding Dabigatran110mgDabigatran150mgWarfarin Dabigatran 110mg vs. Warfarin Dabigatran 150mg vs. Warfarin n RR 95% CI pRR p Total14.6%16.4%18.2% < Major 2.7 % 3.1 % 3.4 % Life- Life-Threatening 1.2 % 1.5 % 1.8 % < Gastro-intestinal 1.1 % 1.5 % 1.0 % <0.001 Connolly et al., NEJM, 2009

103 RR 0.40 (95% CI: 0.27–0.60) p<0.001 (sup) RE-LY: Intra-cranial Bleeding Rates RR 0.31 (95% CI: 0.20–0.47) p<0.001 (sup) Number of events 0,23 % 0,74 % 0,30 % RRR69% RRR60% Connolly et al., NEJM, 2009

104 Targeted inhibition of thrombin Targeted inhibition of thrombin Consistent and predictable anticoagulant effect Consistent and predictable anticoagulant effect How can dabigatran be more effective than warfarin yet cause less bleeding?

105 RE-LY: Secondary Efficacy Outcomes According to Treatment Group N Engl J Med Connolly, et al. N Engl J Med 2009;361: Event Dabigatran 110 mg Dabigatran 150 mg Warfarin Myocardial infarction 0.7%0.7%0.5% Vascular death 2.4%2.3%2.7% All-cause mortality 3.8%3.6%4.1%

106 Chance finding? Chance finding? Warfarin superior to dabigatran for inhibitionof clotting at sites of plaque disruption? Warfarin superior to dabigatran for inhibitionof clotting at sites of plaque disruption? Other factors? Other factors? Why is There More MI with Dabigatran?

107 End point Warfarin Dabigatran 110 mg twice daily RR (95% CI) vs warfarin pDabigatran 150 mg twice daily RR (95% CI) vs warfarin p Stroke/ systemic embolism (%/year) (0.59–1.22) (0.53–1.10)0.14 Hemorrhagic stroke (n) (0.03–0.47) (0.10–0.72)0.009 ICH (n) (0.08–0.47) (0.21–0.79)0.007 RE-LY: Outcomes in Secondary-Prevention Patients with AF by Treatment Assignment Diener HC et al. American Stroke Association International Stroke Conference 2010; February 26, 2010; San Antonio, TX.

108 RE-LY: Cumulative Risk of ALT or AST >3x ULN After Randomization Years of follow-up Dabigatran 110 mg Cumulative risk Dabigatran 150 mg Warfarin N Engl J Med Connolly, et al. N Engl J Med 2009;361:

109 Lower-dose regimen Elderly Elderly Renal insufficiency Renal insufficiency Lower stroke risk (CHADS 2 score of 1) Lower stroke risk (CHADS 2 score of 1) Higher-dose regimen Higher stroke risk (CHADS 2 score 2) Higher stroke risk (CHADS 2 score 2) Which Dose for Which Patient?

110 Camm J.: Oral presentation at ESC on Aug 30th Meta-analysis of Ischemic Stroke or Systemic Embolism W vs placebo W vs W low dose W vs ASA W vs ASA + clopidogrel W vs dabigatran Favours warfarin Favours other treatment

111 What About Trials with Other New Oral Anticoagulants ? ROCKET – Rivaroxaban ROCKET – Rivaroxaban ARISTOTLE – Apixaban ARISTOTLE – Apixaban ENGAGE - Edoxaban ENGAGE - Edoxaban

112 What about other indications?

113 RE-COVER TM Trial Design Objectiveconfirmation of VTE ER 30 days follow up Initial parenteral therapy Single-dummy period Double-dummy period 72 h 6 months End of treatment Until INR 2.0 on two consecutive measurements (8-11 days) Warfarin Warfarin (INR 2.0–3.0) Dabigatran etexilate placebo bid Warfarin placebo Dabigatran etexilate 150 mg bid Warfarinplacebo E= enrolment R= randomization

114 Efficacy and Safety Outcomes Schulman et al., N Engl J Med, 2009 OutcomeDabigatranDabigatran HR (95% CI) Recurrent VTE and VTE-related death 2.4%2.1% 1.10 ( ) Major bleeding 1.6%1.9% 0.82 ( )

115 Is Warfarin Obsolete? New oral anticoagulants are more convenient New oral anticoagulants are more convenient But, warfarin effective when time in therapeutic range is high But, warfarin effective when time in therapeutic range is high

116 Cumulative Risk of Stroke, MI, Systemic Embolism, or Vascular Death Connolly, S. J. et al. Circulation 2008;118: OAC OAC C+A C+A Years Years Event Rate (%) TTR < 65% TTR >= 65% RR=0.93 ( ) p=0.61 RR=2.14 ( ) P= Patients treated at centers with a TTR below or above the study median (65%)

117 Time in Therapeutic Range (TTR) with Warfarin in the RE-LY Trial Group Relative Risk Overall64% VKA Experienced 61% VKA Nave VKA Naïve67%

118 All patients Long-term VKA therapy No Yes Region North America South America Western Europe Central Europe South Asia East Asia Other Dabigatran Better Warfarin Better , , , , , , , , , , Subgroup Patients total no. 110 mg 150 mg Warfarin Dabigatran Hazard Ratio with Dabigatran, 100 mg (95% CI) Hazard Ratio with Dabigatran, 150 mg (95% CI) P Value for Interaction P Value for Interaction Relative Risk of Stroke or Systemic Embolism with According to Geographical Region Connolly et al., NEJM 2009 Dabigatran Versus Warfarin

119 Stable on warfarin Stable on warfarin Renal impairment Renal impairment Severe hepatic disease Severe hepatic disease Poor compliance Poor compliance Who is Not a Candidate for Dabigatran?

120 Management of patients with severe coronary artery disease or recent GI bleeding? Management of patients with severe coronary artery disease or recent GI bleeding? Will short half-life obviate need for antidotes? Will short half-life obviate need for antidotes? Will elimination of monitoring adversely impact patient care? Will elimination of monitoring adversely impact patient care? Unanswered Questions

121 Dabigatran etexilate is superior to warfarin for stroke prevention and non-inferior for VTE treatment Dabigatran etexilate is superior to warfarin for stroke prevention and non-inferior for VTE treatment Dosing of new oral anticoagulants is critical; are the doses of factor Xa inhibitors optimal? Dosing of new oral anticoagulants is critical; are the doses of factor Xa inhibitors optimal? New oral anticoagulants will replace warfarin, but transition likely to be slow New oral anticoagulants will replace warfarin, but transition likely to be slow Conclusions: RE-LY and New, Oral Non- Monitored Anticoagulation

122 Atrial Fibrillation Case Study

123 Mrs. A. is a 78-year-old woman who is taking warfarin for stroke prevention on the background of atrial fibrillation. She also takes ASA 81 mg daily. Mrs. A. is a 78-year-old woman who is taking warfarin for stroke prevention on the background of atrial fibrillation. She also takes ASA 81 mg daily. Her risk factors for stroke include hypertension and type II diabetes mellitus. Her INR control has been erratic with values ranging from 1.5 to 6.8. Her risk factors for stroke include hypertension and type II diabetes mellitus. Her INR control has been erratic with values ranging from 1.5 to 6.8. For the past two weeks, she has had intermittent nosebleeds lasting 5 to 20 minutes. She is anxious to stop warfarin. For the past two weeks, she has had intermittent nosebleeds lasting 5 to 20 minutes. She is anxious to stop warfarin. Atrial Fibrillation Case Study

124 Question 1: What is the best approach for this patient? (a)Stop the warfarin and the ASA (b)Stop the ASA, but continue warfarin (c)Perform CYP2C9 and VKORC1 genotyping to better identify an appropriate warfarin dose (d)Stop the warfarin and add clopidogrel 75 mg daily (e)Continue warfarin and ASA, but monitor the INR more frequently Atrial Fibrillation Case Study

125 The ASA was stopped, but Mrs. A. still complains of nosebleeds. Despite weekly monitoring, her INR continues to range from 1.8 to 4.8. A calculated creatinine clearance is 45 ml/min. Atrial Fibrillation Case Study

126 Question 2: If dabigatran were approved for stroke prevention in patients with atrial fibrillation, what would you likely do at this point? (a)Continue on warfarin (b)Continue on warfarin, but add low-dose vitamin K (c)Switch from warfarin to dabigatran etexilate 110 mg b.i.d. (d)Switch from warfarin to dabigatran etexilate 150 mg b.i.d. (e)Switch from warfarin to ASA and clopidogrel Atrial Fibrillation Case Study

127 Atrial Fibrillation and Thromboembolism Current State of the Art and Science There is a new, quickening rhythm to the pace of research and clinical advances in atrial fibrillation There is a new, quickening rhythm to the pace of research and clinical advances in atrial fibrillation Etiology of AF is multifactorial and we are just beginning to understand the inter-relationship among myriad factors Etiology of AF is multifactorial and we are just beginning to understand the inter-relationship among myriad factors Noninvasive imaging and biomarkers of inflammation and thrombosis can predict clinical events in AF and may help guide therapy Noninvasive imaging and biomarkers of inflammation and thrombosis can predict clinical events in AF and may help guide therapy Risk stratification strategies for AF are useful but imperfect: advances and refinements are required to help define role for non-monitored, oral anticoagulants Risk stratification strategies for AF are useful but imperfect: advances and refinements are required to help define role for non-monitored, oral anticoagulants

128 Atrial Fibrillation and Thromboembolism Current State of the Art and Science Atrial Fibrillation and Thromboembolism Current State of the Art and Science Strategies are being developed to improve the safety and efficacy of vitamin K antagonists (VKAs), but achieving acceptable TTRs remains a challenge Strategies are being developed to improve the safety and efficacy of vitamin K antagonists (VKAs), but achieving acceptable TTRs remains a challenge Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage, and therefore demand special attention Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage, and therefore demand special attention Novel anticoagulants appear to be safer in the elderly population due to their wider therapeutic index, shorter t 1/2, lack of dietary interference, and fewer drug interactions. Novel anticoagulants appear to be safer in the elderly population due to their wider therapeutic index, shorter t 1/2, lack of dietary interference, and fewer drug interactions.

129 Atrial Fibrillation and Thromboembolism Current State of the Art and Science Dabigatran etexilate is superior to warfarin for stroke Dabigatran etexilate is superior to warfarin for stroke prevention and non-inferior for VTE treatment prevention and non-inferior for VTE treatment Dosing strategy for new oral anticoagulants is critical: Dosing strategy for new oral anticoagulants is critical: selecting the appropriate dose in the individual patient to selecting the appropriate dose in the individual patient to achieve ideal balance of stroke prevention and bleeding achieve ideal balance of stroke prevention and bleeding minimization is a work in progress minimization is a work in progress New oral anticoagulants will replace warfarin, and the New oral anticoagulants will replace warfarin, and the transition will impact the landscape of anticoagulation transition will impact the landscape of anticoagulation management management The RE-LY Trial represents the most compelling evidence The RE-LY Trial represents the most compelling evidence to date for revising, reconsidering, and reshaping our to date for revising, reconsidering, and reshaping our current VKA-based paradigm for stroke prevention in AF current VKA-based paradigm for stroke prevention in AF

130 At least four trials evaluating the safety and efficacy of oral, non-monitored anticoagulants for SPAF are in progress: stay tuned At least four trials evaluating the safety and efficacy of oral, non-monitored anticoagulants for SPAF are in progress: stay tuned Atrial Fibrillation and Thromboembolism Current State of the Art and Science Thank You QUESTIONS


Download ppt "New Paradigms and Landscape Changes in Atrial Fibrillation Emerging Perspectives in Thrombosis Mitigation for the Cardiovascular SpecialistApplying Landmark."

Similar presentations


Ads by Google